Department of Biochemistry, University of Stellenbosch, Stellenbosch 7600, South Africa.
Mol Cell Endocrinol. 2013 Sep 5;377(1-2):135-46. doi: 10.1016/j.mce.2013.07.006. Epub 2013 Jul 13.
Adrenal C19 steroids, dehydroepiandrostenedione (DHEA(S)) and androstenedione (A4), play a critical role in castration resistant prostate cancer (CRPC) as they are metabolised to dihydrotestosterone (DHT), via testosterone (T), or via the alternate 5α-dione pathway, bypassing T. Adrenal 11OHA4 metabolism in CRPC is, however, unknown. We present a novel pathway for 11OHA4 metabolism in CRPC leading to the production of 11ketoT (11KT) and novel 5α-reduced C19 steroids - 11OH-5α-androstanedione, 11keto-5α-androstanedione, 11OHDHT and 11ketoDHT (11KDHT). The pathway was validated in the androgen-dependent prostate cancer cell line, LNCaP. Androgen receptor (AR) transactivation studies showed that while 11KT and 11OHDHT act as a partial AR agonists, 11KDHT is a full AR agonist exhibiting similar activity to DHT at 1nM. Our data demonstrates that, while 11OHA4 has negligible androgenic activity, its metabolism to 11KT and 11KDHT yields androgenic compounds which may be implicated, together with A4 and DHEA(S), in driving CRPC in the absence of testicular T.
肾上腺 C19 类固醇、脱氢表雄酮 (DHEA(S)) 和雄烯二酮 (A4) 在去势抵抗性前列腺癌 (CRPC) 中发挥着关键作用，因为它们可以通过睾酮 (T) 代谢为二氢睾酮 (DHT)，或者通过替代的 5α-二酮途径代谢，绕过 T。然而，CRPC 中的肾上腺 11OHA4 代谢是未知的。我们提出了一种新的 CRPC 中 11OHA4 代谢途径，导致产生 11ketoT (11KT) 和新型 5α-还原 C19 类固醇-11OH-5α-雄烷二酮、11keto-5α-雄烷二酮、11OHDHT 和 11ketoDHT (11KDHT)。该途径在雄激素依赖性前列腺癌细胞系 LNCaP 中得到了验证。雄激素受体 (AR) 转激活研究表明，虽然 11KT 和 11OHDHT 作为部分 AR 激动剂起作用，但 11KDHT 是完全的 AR 激动剂，在 1nM 时表现出与 DHT 相似的活性。我们的数据表明，虽然 11OHA4 几乎没有雄激素活性，但它代谢为 11KT 和 11KDHT 会产生雄激素化合物，这些化合物可能与 A4 和 DHEA(S)一起，在没有睾丸 T 的情况下参与推动 CRPC 的发展。
